A key event in the pathogenesis is the production of antibodies of the IgE class. Hypergammaglobulinemia E results from loss of immunoregulation. More specifically, T lymphocyte abnormalities have been reported in a number of pathologic hyper IgE conditions and are the object of much research aiming at developing pharmaceutical compounds that will prevent atopic allergy and asthma.
TCR recognize peptide fragments bound to major histocompatibility complex (MHC) molecules and relay this information to the interior of the T cell via adapter proteins. One of these, the adapter LAT (Linker for Activation of T cells), coordinates the assembly of signaling complexes through multiple tyrosine residues within its intracytoplasmic segment. Upon TCR-induced phosphorylation, each of these tyrosine residues manifests some specialization in the signaling proteins it recruits. Studies on cell lines showed that mutation of tyrosine 136 (Y136) selectively eliminates binding of phospholipase Cγ1 (PLC-γ1) whereas the simultaneous mutation of Y175, Y195 and Y235 results in loss of binding of downstream adapters Gads and Grb-2 (Lin and Weiss, 2001; Samelson et al, 1999; Zhang et al, 2000). Studies of LAT “knock in” mutant mice presenting the mutation of the four distal tyrosine residues of LAT in phenylalanine, called 4YF mice, showed that the murine T cell development was completely blocked (Sommers et al, 2001). Hence, their thymocyte development was arrested at the immature CD4− CD8− stage and no mature T cells were present.
The present invention now provides genetic evidence that LAT exerts an unanticipated and surprising inhibitory function on the differentiation of CD4 helper T (TH) cells into TH2 cells.
Mice homozygous for the mutation of a single LAT tyrosine (LAT Y136F) results in mice that show a precocious and spontaneous accumulation of polyclonal TH2 cells, which chronically produce large amounts of interleukins 4, 5, 10 and 13. This exaggerated TH2 differentiation leads in turn to tissue eosinophilia and to the maturation of massive numbers of plasma cells secreting IgE and IgG1 antibodies (see FIG. 1). Thus, in addition to known positive signaling, LAT also appears essential for establishing inhibitory signals that control T cell homeostasis.
Mice for the composite mutation of the three distal LAT tyrosines (LAT Y175F+Y195F+Y235F) prevents the development of T cells expressing alpha/beta T cell receptor. However, it allows the development of T cells expressing gamma/delta T cell receptors, and their accumulation in the periphery (see FIG. 9). These polyclonal gamma/delta T cells chronically produce large amounts of interleukins 4, 5, 10 and 13 (i.e. they present blatant TH2 phenotype). This exaggerated TH2-type differentiation of gamma/delta T cells leads in turn to the maturation of massive numbers of plasma cells secreting IgE and IgG1 antibodies (see FIGS. 10 and 11).